Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Mol Syst Biol. 2011 May 10;7:488. doi: 10.1038/msb.2011.20.
Many biological networks respond to various inputs through a common signaling molecule that triggers distinct cellular outcomes. One potential mechanism for achieving specific input-output relationships is to trigger distinct dynamical patterns in response to different stimuli. Here we focused on the dynamics of p53, a tumor suppressor activated in response to cellular stress. We quantified the dynamics of p53 in individual cells in response to UV and observed a single pulse that increases in amplitude and duration in proportion to the UV dose. This graded response contrasts with the previously described series of fixed pulses in response to γ-radiation. We further found that while γ-triggered p53 pulses are excitable, the p53 response to UV is not excitable and depends on continuous signaling from the input-sensing kinases. Using mathematical modeling and experiments, we identified feedback loops that contribute to specific features of the stimulus-dependent dynamics of p53, including excitability and input-duration dependency. Our study shows that different stresses elicit different temporal profiles of p53, suggesting that modulation of p53 dynamics might be used to achieve specificity in this network.
许多生物网络通过一种共同的信号分子对各种输入做出响应，从而触发不同的细胞结果。实现特定输入-输出关系的一种潜在机制是针对不同的刺激触发不同的动态模式。在这里，我们专注于 p53 的动力学，p53 是一种在细胞应激时被激活的肿瘤抑制因子。我们量化了单个细胞对 UV 的反应中的 p53 动力学，观察到一个单一的脉冲，其幅度和持续时间与 UV 剂量成正比而增加。这种分级响应与之前描述的针对γ辐射的一系列固定脉冲形成对比。我们进一步发现，虽然 γ 触发的 p53 脉冲是可激发的，但 p53 对 UV 的反应不是可激发的，并且依赖于输入感应激酶的持续信号。通过数学建模和实验，我们确定了反馈回路，这些回路有助于 p53 对刺激的动力学的特定特征，包括兴奋性和输入持续时间依赖性。我们的研究表明，不同的应激会引发不同的 p53 时间分布，这表明调节 p53 动力学可能用于实现该网络中的特异性。
